Effects of nisoldipine and lisinopril on microvascular dysfunction in hypertensive Type I diabetes patients with nephropathy

1. Our objective was to compare the effect of a long-acting calcium antagon ist (nisoldipine) compared with an angiotensin-converting enzyme inhibitor (lisinopril) on the non-neurogenic regulation of the microvascular blood fl ow in hypertensive Type I diabetes patients with diabetic nephropathy. 2. We performed a 1-year double-blind, double-dummy randomized controlled s tudy comparing nisoldipine (20-40 mg once daily) with lisinopril (10-20 mg once daily) in 48 hypertensive Type I diabetes patients with diabetic nephr opathy. For comparison, 22 age-matched normotensive healthy control subject s were included. Measurements were performed at baseline and after year of antihypertensive treatment. The minimal vascular resistance and distensibil ity (stiffness) of resistance vessels in skin and skeletal muscle were meas ured using the local isotope washout method. 3. Mean arterial pressure was reduced to the same extent in both groups: ni soldipine, 113 +/- 2.1 to 105 +/- 1.6 mmHg (P < 0.001); lisinopril, 110 +/- 2.7 to 101 +/- 2.1 mmHg (P < 0.002) (controls, 88 +/- 2.2 mmHg; P < 0.0001 compared with diabetic patients). Nisoldipine improved the skin vascular d istensibility from 28 +/- 3.3 to 43 +/- 3.8% (P < 0.005) and decreased skin minimal vascular resistance from 16.9 +/- 1.0 to 13.6 +/- 0.8 mmHg.ml(-1). min.100 g (P < 0.02). Lisinopril had no significant effect on skin vascular distensibility (40 +/- 4.0% and 41 +/- 4.4%), but minimal vascular resista nce tended to diminish (18.1 +/- 0.9 to 15.8 +/- 1.3 mmHg.ml(-1).min.100 g (P = 0.09). Nisoldipine significantly increased the skin distensibility (P = 0.05) after 1 year of antihypertensive treatment compared with lisinopril . 4, The central group had a skin vascular distensibility of 54 +/- 3.2% and a minimal vascular resistance of 10.8 +/- 0.7 mmHg.ml(-1).min.100 g, both s ignificantly different from the values in the diabetic groups (P < 0.0001 f or all). Skeletal muscle vascular distensibility was unaltered after 1 year of treatment with both nisoldipine (22 +/- 3.3 % and 19 +/- 2.7%) and lisi nopril (19 +/- 2.1 % and 24 +/- 2.5%), but was reduced compared with a cont rol value of 43 +/- 3.7% (P < 0.0001 for diabetes patients versus controls) . However, neither nisoldipine nor lisinopril had any effect on the increas ed minimal vascular resistance or the reduced skeletal muscle distensibilit y. 5. Enhanced thickening of the basement membranes of the terminal arteriolar wall was found in skin biopsy specimens in 91% of diabetic patients and 38 % only in control subjects (P < 0.000001 both before and after treatment fo r diabetic patients versus controls). There was no significant effect of an tihypertensive treatment on arteriolar hyalinosis. 6. The reduction in systemic blood pressure was identical during 1 year of treatment with nisoldipine or lisinopril. The abnormal arteriolar stiffness was more pronounced in the group treated with nisoldipine than with lisino pril and only nisoldipine compared with lisinopril improved the abnormal ar teriolar stiffness and minimal vascular resistance in the skin. This sugges ts that nisoldipine can reverse the peripheral skin perfusion and thereby i mprove the local protection against development of ischaemic skin lesions i n Type I diabetes patients with clinical diabetic nephropathy.